PROJECT SUMMARY Immunologically-mediated adverse drug reactions (IM-ADR) comprise less than 20% of adverse drug reactions, but contribute disproportionately to the morbidity, mortality and uncertainty of drug development. The severest of IM-ADR are Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), that are life- threatening emergencies representing the same disease across a spectrum of severity that affects 60,000 patients per year globally at an incidence of 5 cases per 1,000,000 in the United States. The current evidence base for management of SJS/TEN is limited as there are no randomized controlled trials comparing supportive care with other treatment interventions. Strong associations between the HLA Class I allele HLA-B*15:02 has led to implementation of cost-effective pre-treatment genetic screening programs in many Southeast Asian countries that have successfully reduced the incidence of carbamazepine SJS/TEN. However, the lower prevalence (<1%) and negative predictive value of this HLA allele in European American, Hispanic American, and African American populations, and the lack of currently defined HLA associations with drugs commonly used and associated with SJS/TEN in the United States has left many evidence gaps and implementation hurdles. The scientific premise of our study is to address the critical knowledge gaps that currently limit the optimal care of patients with SJS/TEN. We propose a multicenter double-blind randomized controlled assessment of two systemic therapies and supportive care. We further aim to harness the strength of our rigorous design to discover new genetic and biological markers as well as cellular and molecular signatures that will provide important mechanistic insights into strategies for the prevention, early diagnosis, and treatment of SJS/TEN. In Specific Aim 1 we will establish the most clinically effective therapy for SJS/TEN. A multi-centered, double-blind randomized controlled trial with a planned enrollment of 267 patients over 4 years will be undertaken to evaluate which of supportive care, cyclosporine or etanercept leads to the greatest reduction in time to complete re-epithelialization. In Specific Aim 2 we will use genome wide sequencing, high resolution HLA sequencing, transcriptomic, proteomic and cytokine profiling to identify genetic and biological markers that predict risk and outcome for SJS/TEN. In Specific Aim 3 we will gain important insights into the immunopathogenesis of SJS/TEN using innovative single-cell technologies to characterize the T-cell receptor repertoire and transcriptomic profile of the immune effector cells in the skin and blister fluid of patients with drug-associated SJS/TEN. Our study will be the first to examine in a randomized controlled design both management and mechanisms of SJS/TEN. We anticipate that this will lead to new ways to prevent, diagnosis and treat SJS/TEN, and will create a roadmap and evidence-base for studies in serious immunologically- mediated adverse drug reactions and other immunologically-mediated diseases.